Crystal structure of linoleate 13R-manganese lipoxygenase in complex with an adhesion protein

Chen, Yang; Wennman, Anneli; Karkehabadi, Saeid; Engström, Åke; Oliw, Ernst H.

doi:10.1194/jlr.m069617

Cited by 21 publications

(19 citation statements)

References 50 publications

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“…The two manganese lipoxygenases (F2QXM5 and MNLOX) exhibit a distinctive behavior (higher mobility) compared to all other LOXs at two regions, around site 2 (I247-F264) and around H610 ( green arrow ). The preferred substrate for manganese LOXs from Ascomycete fungi is LA, 66 while for the mammalian LOXs and pLoxA it is AA. Overall, evolutionarily close LOXs seem to also share similar structural dynamics.…”

Section: Resultsmentioning

confidence: 99%

Characterization of Differential Dynamics, Specificity, and Allostery of Lipoxygenase Family Members

Mikulska-Ruminska

Shrivastava²,

Krieger³

et al. 2019

J. Chem. Inf. Model.

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Accurate modeling of structural dynamics of proteins and their differentiation across different species can help us understand generic mechanisms of function shared by family members and the molecular basis of the specificity of individual members. We focused here on the family of lipoxygenases, enzymes that catalyze lipid oxidation, the mammalian and bacterial structures of which have been elucidated. We present a systematic method of approach for characterizing the sequence, structure, dynamics, and allosteric signaling properties of these enzymes using a combination of structure-based models and methods and bioinformatics tools applied to a data set of 88 structures. The analysis elucidates the signature dynamics of the lipoxygenase family and its differentiation among members, as well as key sites that enable its adaptation to specific substrate binding and allosteric activity.

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Section: Resultsmentioning

confidence: 99%

Characterization of Differential Dynamics, Specificity, and Allostery of Lipoxygenase Family Members

Mikulska-Ruminska

Shrivastava²,

Krieger³

et al. 2019

J. Chem. Inf. Model.

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“…The sixth ligand of the octahedrally coordinated iron, which is positioned towards the putative substrate-binding channel, is a water (Fe 2+ -H 2 O) or hydroxide molecule (Fe 3+ -OH) acting as a catalytic base for hydrogen abstraction during catalysis. In contrast to MnLOX, for which a slightly altered metal coordination geometry was reported 14 , 15 , the coordination of the iron cofactor in CspLOX2 resembles strongly the one of the prototypical soybean LOX1 or the 8 R -LOX from P. homomalla (Supplemental Fig. 1 ).…”

Section: Resultsmentioning

confidence: 93%

“…Since CspLOX2 harbors iron in the active site and is inactive with manganese, the determinant for this unusual reaction cannot be, at least for CspLOX2, the type of metal in the active site 13 . The recently published structures of MnLOX revealed that the geometry of manganese coordination in the active site differs from the iron coordination in FeLOX 14 , 15 . The coordination geometry of CspLOX2, however, resembles those of other FeLOX (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 99%

“…These LOX are mainly fungal enzymes that contain manganese in the active site 9 – 11 , but also the iron-containing enzyme CspLOX2 from the cyanobacterium Cyanothece PCC8801 forms (11 R )-hydroperoxy octadecadienoic acid (11-HPODE) as major product 12 , 13 . Even though the first enzyme with bis-allylic products was reported in 1998 9 and the first structures of a manganese-containing LOX were recently published 14 , 15 , the underlying structural factors responsible for this unusual reaction could not yet be determined.…”

Section: Introductionmentioning

confidence: 99%

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Lipoxygenase 2 from Cyanothece sp. controls dioxygen insertion by steric shielding and substrate fixation

Newie¹,

Neumann

Werner

et al. 2017

Sci Rep

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The biological function of lipoxygenases depends on the regio and stereo specific formation of fatty acid-derived hydroperoxides and different concepts exist to explain the mechanism that directs dioxygen to a specific carbon atom within the substrate. Here, we report the 1.8 Å resolution crystal structure of a cyanobacterial lipoxygenase that produces bis-allylic hydroperoxides (CspLOX2). Site directed mutagenesis experiments combined with computational approaches reveal that residues around the active site direct dioxygen to a preferred carbon atom and stereo configuration in the substrate fatty acid. Modulating the cavity volume around the pentadiene system of linoleic acid shifted the product formation towards 9S-, 9R-, 13S- or 13R-hydroperoxides in correlation with the site of mutation, thus decreasing the amount of the bis-allylic 11R-hydroperoxide. Decreasing the channel size of a 9R-lipoxygenase (CspLOX1) on the other hand could in turn induce formation of the bis-allylic 11R-hydroperoxide. Together this study suggests that an active site clamp fixing the pentadiene system of the substrate together with steric shielding controls the stereo and regio specific positioning of dioxygen at all positions of the reacting pentadiene system of substrate fatty acids.

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“…Two fungal LOXs have emerged as model enzymes, including that from M. oryzae (MoLOX) and G. graminis (GgLOX); structures of both enzymes have been solved [ 111 , 114 ]. Besides the obvious lack of a PLAT domain, another divergent structural feature is an elongated helix 2 that traverses residues 79–119 ( Figure 9 A, salmon).…”

Section: Location Of the Fatty Acid Allosteric Sitementioning

confidence: 99%

Fatty Acid Allosteric Regulation of C-H Activation in Plant and Animal Lipoxygenases

Offenbacher

Holman

2020

Molecules

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Lipoxygenases (LOXs) catalyze the (per) oxidation of fatty acids that serve as important mediators for cell signaling and inflammation. These reactions are initiated by a C-H activation step that is allosterically regulated in plant and animal enzymes. LOXs from higher eukaryotes are equipped with an N-terminal PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain that has been implicated to bind to small molecule allosteric effectors, which in turn modulate substrate specificity and the rate-limiting steps of catalysis. Herein, the kinetic and structural evidence that describes the allosteric regulation of plant and animal lipoxygenase chemistry by fatty acids and their derivatives are summarized.

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Crystal structure of linoleate 13R-manganese lipoxygenase in complex with an adhesion protein

Cited by 21 publications

References 50 publications

Characterization of Differential Dynamics, Specificity, and Allostery of Lipoxygenase Family Members

Characterization of Differential Dynamics, Specificity, and Allostery of Lipoxygenase Family Members

Lipoxygenase 2 from Cyanothece sp. controls dioxygen insertion by steric shielding and substrate fixation

Fatty Acid Allosteric Regulation of C-H Activation in Plant and Animal Lipoxygenases

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